Nu-arylsubstituted alkenones and alkanols of arylamino alkanols



United States Patent 3,395,143 N ARYLSUBSTITUTED ALKENONES AND ALKANOLS 0F ARYLAMINO ALKANOLS Kurt Thiele, Frankfurt am Main, and Klaus Posselt, Bergen-Enkheim, Germany, assignors to Deutsche Goldund Silber-Scheideanstalt vormals Roessler, Frankfurt am Main, Germany No Drawing. Filed Aug. 23, 1965, Ser. No. 481,901

Claims priority, applicatigrsi fiesrmany, Aug. 29, 1964,

10 Claims. ci. 260-240) ABSTRACT OF THE DISCLOSURE Compounds possessing action on the heart blood circulation of the formula:

NAlkO 01 R"OOCAlkO- 6 in which Alk is a straight or branched alkylene with 1 to 6 carbon atoms, each of R and R are hydrogen or lower alkyl groups when taken individually and when taken together are lower alkylene forming a to 7 membered ring with the nitrogen atom and R is lower alkyl, each of R R and R are hydrogen or methyl, Ar is an aromatic radical which may contain a condensed ring system, such as, phenyl or naphthyl, which also may be partially or totally saturated, including mono and poly cyclic cycloalkyl compounds, Y is R and R each are hydrogen, halogen, alkyl hydroxy or methoxy and n is an integer of from 1 to 3.

DETAILED DESCRIPTION OF THE INVENTION INCLUDING PREFERRED EMBODIMENTS The present invention relates to novel pharmaceutically valuable compounds described above.

The novel compounds according to the invention possess a very marked action on the heart blood circulation. They are indicated for treatment of coronary spasms and for improving the coronary blood flow as evidenced by tests on the Langendorif guinea pig heart and the results of toxicological tests. The coronary dilating effect on guinea pig hearts is especially noteworthy. In a dosage range of 10-320 'y/heart (single injection) the compounds effect a marked increase in coronary blood flow of long lasting duration of, for example, to 90 minutes. The compounds are of low toxicity. The LD upon oral administration to mice is between 1.5 and 8 g./kg.

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The compounds according to the invention can be produced by reacting a compound of the formula:

with a compound of the formula:

HNOH-CH- 1'1 1's in R in the presence of formaldehyde or a compound yielding formaldehyde in an inert solvent such as alcohol, glacial acetic acid or dioxane, at the boiling point of the inert solvent or temperatures between about and 120 C.

The conversion of the keto group into an alcohol group, if desired, can be effected with a reducing agent, such as, lithium aluminum hydride or sodium borohydride.

The compounds according to the invention contain optically active carbon atoms and usually are produced as racemates. The latter can be separated into the optically active isomers, for example, by reaction with an optically active acid and fractional crystallization. In many instances, however, it is possible to employ optically active compounds as the starting compounds.

The following examples will serve to illustrate the compounds according to the invention with reference to a number of representative specific embodiments thereof.

The symbol X given in the structural formulae in a number of the examples signifies the radical EXAMPLE 1 5-[3-phenyl-3-hydroxy-propy1-(2)-amino]-1-phenylpenten-( 1 -one- (3) 5- 3-phenyl-3 -hydroxy-propyl- (2 -amino] -1- (4- methoxyphenyl)-penten-(1)-one-(3) 17.6 g. of anisal acetone, 18.7 g. of l-norephedrine- HCl and 4 g. and 1.5 g. of paraformaldehyde were reacted in 75 ml. of isopropanol and processed as in Example 1. The HCl salt was recrystallized from methanol. The melting point thereof was l186 C.

EXAMPLE 3 5-[3-phenyl-3-hydroxy-propyl-(2)-amino]-1-(3,4- methylene dioxy phenyl) -penten-( 1 -one- (3 3 38 g. of piperonal acetone, 37.4 g. of l-norephedrine- HCl and 8 g. of paraformaldehyde were boiled under reflux in 100 ml. of isopropanol for /2 hour. The reaction mixture was diluted with 200 ml. of acetone and cooled down. The HCl salt was recrystallized from 90% methanol. Its melting point was 198199 C.

EXAMPLE 4 -[3-phenyl-3-hydroxy-propyl-(2)-amino]-1-(3-nitrophenyl)-penten(1)-one-(3) 19.1 g. of m-nitrobenzene, 18.7 g. of l-norephedrine- HCl and 4 g. of paraformaldehyde were boiled under reflux with 75 ml. of isopropanol on a water bath for 1 hour. The reaction mixture was diluted with 150 ml. of acetone and the HCl salt recrystallized from methanol. Its melting point was 202-204 C.

EXAMPLE 5 5 3-phenyl-3 -hydroxy-propyl- 2 -amino] -1- (4-chlorophenyl)-penten-(1)-one-(3) 14.5 g. of p-chlorobenzal acetone, 15.0 g. of l-norephedrine-HCl and 3 g. of paraformaldehyde were refluxed with 100 ml. of isopropanol on a water bath for /2 hour. Then an additional 1.5 g. of paraformaldehyde were added and the mixture refluxed for a further hour. The reaction mixture was then diluted with 200 ml. of acetone and the HCl salt recrystallized from methanol. Its melting point was 191-192 C.

EXAMPLE 6 5 [3 -phenyl-3-hyclroxy-propyl- (2) -amino] 'l-naphthyl- (1)-penten-( 1 -one- (3) 33 g. of a-naphthal acetone, 31.2 g. of l-norephedrine- HCl and 6 g. plus 1.5 g. of paraformaldehyde were reacted in 150 ml. of isopropanol and processed in a manner analogous to that of Example 1. The HCl salt was recrystallized from glacial acetic acid. Its melting point was 185 C.

EXAMPLE 7 5- 3-phenyl-3-hydroxy-propyl-2-amino] -1-(3 ,4-dime'thoxy phenyl -penten-( 1 -one- 3) (II-Id 4 EXAMPLE 8 5-[3-phenyl-3-hydroxy-propyl-2-amino]-l-[1,1,3-trimethyl cyclohexene-(2)-yl-(2) ]-penten-( 1 )-one-(3) GHQ/CH3 H1 385 g. of B-ionone, 37.5 g. of l-norephedrine-HCl and 6 g. plus 6 g. of paraformaldehyde in ml. of isopropanol were reacted and processed analogously to Example 1. The HCl was recrystallized from isopropanol. Its melting point was C.

EXAMPLE 9 5 3 -phenyl-3-hydroxy-propyl-(2)-amino] -1-(4-hydroxy- 3-methoxy-phenyl)-penten-( 1 )-one-(3 28.8 g. of vanillal acetone, 28 g. of l-norephedrine-HCl and 4.5 g. of paraformaldehyde were refluxed in 150 ml. of isopropanol for 1 hour on a water bath. Then 3 further grams of paraformaldehyde were added and the mixture refluxed for another /2 hour. The reaction mixture was stirred into 200 ml. of ethyl acetate and the HCl salt recrystallized from ethanol. Its melting point was 182 C.

EXAMPLE 10 5-[3-phenyl-3-hydroxy-propyl-(2)-amino]-1-(3-methoxyphenyl -penten-( 1 -one- 3) CHaO 52.8 g. of m-methoxy benzal acetone, 56.2 g. of l-norephedrine-HCl and 9 plus 9 g. of paraformaldehyde were reacted and processed analogously to Example 9. The HCl salt was recrystallized from isopropanol. Its melting point was 186 C.

EXAMPLE 11 5-[ 3-phenyl-3-hydroxy-propyl-(2)-amino1-1-(3-nitro-4- methoxy-phenyl)-penten-(1)-one-(3) CHsO-Q-X 33 g. of 3-nitro-4-methoxy-benzal acetone, 28 g. of l-norephedrine-HCI and 4.5 g. of paraformaldehyde were refluxed in 700 ml. of isopropanol on a water bath. After one hour another 4.5 g. of parafomaldehyde were added and the mixture refluxed for a further hour. The melting point of the I-ICl salt was 204 C.

EXAMPLE 12 5-[3-phenyl-3-hydroxy-propyl-(2)-amino]-1-(3- nitrophenyl)-3-hydroxy-penten-( 1 20 g. of 5-[3-phenyl-3-hydroxy-propyl-2-amino]-1(3- nitrophenyl)penten-(1)-one-(3) were reduced into 6 g. of sodium borohydride in 350 ml. of ethanol at room temperature. After 1 hour the reaction mixture was decomposed with addition of 150 ml. of water. The solvent was then distilled 01f and the residue taken up in ether. The HCl salt was precipitated with ethanolic HCl and recrystallized from isopropanol. Its melting point was 147 C.

6 EXAMPLE 13 65 g. of p-carbethoxymethoxy benzal acetone, 49 g. of

l-norephedrine-HCI and 8 g. plus 8 g. of paraformaldehyde in 400 ml. of isopropanol were reacted analogously to Example 1. The HCl salt was recrystallized from ethanol. g. of the product with a melting point of 188 C.

7-[3-phenyl-3-hydroxy-propyl-(2)-amino]-1-phenylheptadiene-( 1,3 )-one-(5 were obtained. Q-(CH=CH)aCO-OH2-CH2NHCHCH3 EXAMPLE 13 34.4 g. of cinnamylidene acetone, 37.5 g. of l-norephed- 5-[3-(4-hydroxy-phenyl)-3-hydroxy-propyl-(2)-amin0]- rine-HCl and 6 g. plus 3 g. of paraiormaldehyde in 150 1-(4-hydroxy-3-methoxy-phenyl)-penten-(1)-oue-(3) ml. of isopropanol were reacted and processed analo- 96 g. of 4-acetoxy-3-methoxy-benzal acetone, 83.5 g. gously to Example 1. The HCl salt was recrystillized of 1-p-hydroxynorephedrine-HC1 and 12.3 g. plus 12.3 g. from ethanol. 22 g. of the HCl salt of a melting point of of paraformaldehyde in 1100 ml. of ethanol were reacted 190 C. were obtained. analogously to Example 14 and the acetoxy compound then deacetylated in 500 ml. of 90% ethanol and 20 ml.

EXAMPLE 14 20 come. HCl. The HCl salt was recrystallized from. iso- 5-[3-phenyl-3-hydroxy-propyl-(2)-amino]-1-(4-hydroxypropanol. 42 g. of the product with a melting point of phenyl)-penten-(1)-one-(3) 196 C. were obtained.

HOG}: 2 EXAMPLE l9 0 5- 3-phenyl-3-hydr0xy-propyl- (2) -amino] -1- (3 -bromo- 19 g. of p-acetoxy benzal acetone, 18.7 g. of l-nor- 4-methoxy-phenyl)-penten-(1)-one-(3) ephedrine-H01 and 3 g. plus 3 g. of paraformaldehyde 1n 75 ml. of isopropanol were reacted and processed anald gously to Example 1. The HCl salt of the p-acetoxy com- I pound was deacetylated by boiling for 1 hour in 90% Br ethanol with the addition of 1% of HCl. The solution The HCl salt of this compound was produced analowas concentrated and the precipitated HCl salt recrystalgously to Example 1 from 22 g. of m-bromoanisal acelized from ethanol. 11 g. of the product with a melting tone, 16.7 g. of l-norephedrine-HCI and 5.4 g. of parapoint of 198 C. were obtained. formaldehyde in 120 ml, of isopropanol and recrystallized from 90% ethanol. 9 g. of the product with a melting EXAMPLE 1S point of 195 C. were obtained. [3-phenyl-3-hydroxy-propyl-(2) -amino]-1- 4- isopropyl-phenyl) -penten-( 1 -one- 3) EXAM 20 CH3 Y -P py1-2-amin -1- 4- EC methyl-amino 3) 54 g. of isopropyl benzal acetone, 54 g. of l-norephedrine-HCl and 6 g. plus 3 g. of paraformaldehyde in 150 ml. of isopropanol were reacted and processed analo- CH gously to Example 1. The HCl salt was recrystallized 3 from isopropanol. 15 g. of the product with a melting OCHTCH1CHTN point of 185 C. were obtained. CH;

The dihydrochloride of this compound was prepared EXAMPLE 16 analogously to Example 1 from 56 g. of 4-(3-dimethyl- 5-[3-phenyl-3-hydroxy-propyl-(2)-am1n0]-1-[3-n1tro-4- aminopro oxy)-benzal acetone-HCI, 37 g. of l-norephedhydroxy-phenyl]-penten-(1)-one-(3) rine-HCI and 12 g. of paraformaldehyde in 200 ml. of isopropanol and recrystallized from glacial acetic acid. Its melting point was 205 C.

EXAMPLE 21 50 g. of 4-acetoxy-3-nitro-benzal-acetone, 37.5 g. of 1- E i/ Y Y-P PY -(P- Y norephedrine-HCI and 6 g. plus 6 g. of paraformaldehyde P -(U- -Q) in 200 ml. of isopropanol were reacted analogously to 60 Example 14 and the resulting acetoxy compound deacetyl- -Q ated in 300 ml. of 80% ethanol and 10 ml. cone. HCl. The HCl salt was recrystallized from ethanol. The yield The hydrochlonde of thls Compound was Prepared of the roduct was 14 .and its meltin out was 188 C. analogously to Example 1 from 32 of tolylidene acep g g p 1 tone, 39 g. of l-norephedrine-HCI and 6 g. plus 6 g. of

EXAMPLE 17 paraformaldehyde in 150 ml. of isopropanol and recrystal- 5 [3 pheny1 3 hydroxy pmpyl (z) amino] 1 (4 carbeth lized from methanol. 36 g. of the product with a melting oxy methoxy phenyl) penten (1) one (3) point of 188 C. were obtained.

X EXAMPLE 22 I 5-[3-phenyl-3-hydroxy-propyl-(2)-amino]-1- (4- chlorophenyl)-3-hydroxy-pentene-(1 11 g. of -[phenyl-3-hydroXy-propyl-(2)-amino]-l-(4- chlorophenyl)-penten-(l)-one-(3)-HCl were suspended in 100 ml. of ethanol and reduced with a solution of 2 g. of sodium borohydride in 50 ml. of ethanol. After 1 hour m1. of NaOH (10%) were added, the solvent distilled off and the residue taken up in ether. The hydrochloride was precipitated from the ether solution by addition of isopropanolic HCl and recrystallized from ethanol. 9 g. of the product with a melting point of 192 C. were obtained.

EXAMPLE 23 5- [3-pheny1-3-hydroxy-propyl-( 2) -amino] 1- (4-methoxy- 3-chlo1'ophenyl)-penten-(1)-one-(3) 9 g. of m-chloroanisal acetone, 7.1 g. of l-norephedrine-HCl and 1.1 g. plus 1.1 g. of paraformaldehyde in 120 ml. of isopropanol were reacted analogously to Example 1. The HCl salt was recrystallized from ethanol. 4 g. of the product with a melting point of 202 C. were obtained.

EXAMPLE 24 5-[3-phenyl-3-hydroxy-propyl-(2)-amino]-l-(4 acetaminophenyl -penten-( 1 -one- (3) The hydrochloride of this compound was prepared analogously to Example 1 from 10 g. of pacetamino benzal acetone, 9.2 g. of l-norephedrine-HCI and 1.5 g. plus 1.5 g. of paraformaldehyde in 150 m1. of isopropanol and recrystallized from 90% ethanol. 8 g. of the product with a melting point of 218-219 C. were obtained.

EXAMPLE 5- [3-phenyl-3-hydroxy-propyl- (2 -amino] -lt 3- trifluoro-methyl-phenyl) -penten-( 1 -on-e- 3 CFa The hydrochloride of this compound was prepared analogously to Example 1 from 13.0 g. of m-trifiu0romethyl benzal acetone, 11.4 g. of l-norephedrine-HCI and r 1.8 g. plus 1.8 g. of paraformaldehyde in 130 ml. of isopropanol and recrystallized from isopropanol. 6 g. of the product with a melting point of 192 C. were obtained.

EXAMPLE 26 5 [3 phenyl 3 hydroxy propyl (2) amino] 1- {6.6 dimethyl bicyclo [3,1,1] heptene (2) y]- (2)} -penten- (1) one- (3) g. 1 {6.6 dimethyl-bicyclo-[3,l,1]-hepten-(2)-yl- (2)}-butene-(l)-one (3), 34 g. of l-norephedrine-HCI and 5.1 g.+5.1 g. of paraformaldehyde in 250 m1. of isopropanol were reacted analogously to Example 1. The hydrochloride was recrystallized from ethanol with addition of water. 22 g. of the product with a melting point of 224 C. were obtained.

8 We claim: 1. A compound of the formula R1 R R -1 kr(CH=CH)nY-CHCH -NCHCH-( iv 1'1 iv t la R! wherein R and R taken individually are each selected from the group consisting of hydrogen, chlorine, bromine, lower alkyl, hydroxyl, lower alkoxy, nitro, amino, diloweralkyl amino, acetylamino and trifiuoro methyl and when taken together are methylene dioxy, R is selected from the group consisting of hydrogen, chlorine, bromine, lower alkyl, hydroxyl, lower alkoxy, nitro, amino, dilower amino, acetylamino, trifluoromethyl,

in which Alk is an alkylene group of 1-6 carbon atoms, R and R taken individually are each selected from the group consisting of hydrogen and lower alkyl and R is lower alkyl, each of R R and R are selected from the group consisting of hydrogen and methyl, Ar is selected from the group consisting of saturated, unsaturated and aromatic mono-nuclear and bi-nuclear condensed hydrocarbon radicals in which the individual rings have 4 to 6 carbon atoms, Y is selected from the group consisting of each of R and R are selected from the group consisting of hydrogen, chlorine, bromine, lower alkyl, hydroxyl and methoxy and n is an integer from 1 to 3.

2. The compound of claim 1 in which Ar is phenyl.

3. 5 [3 phenyl 3 hydroxy propyl (2) amino] 1 (3,4 methylene dioxy phenyl) penten (1) one- (3).

4. 5 [3 phenyl 3 hydroxy propyl 2) amino} 1- (3 nitro phenyl) penten (1) one (3).

5. 5 [3 phenyl 3 hydroxy propyl (2) amino] 1- (4 chloro phenyl) penten (1) one (3).

6. 5 [3 phenyl 3 hydroxy propyl (2) amino] 1- naphthyl-'(1)- penten (1) one (3).

7. 5 [3 phenyl 3 hydroxy propyl 2 amino] 1- [l,1,3 trimethyl cyclo hexene (2) yl (2)] penten- '(1) -one-*(3).

8. 5 [3 phenyl 3 hydroxy propyl (2) amino] 1 (4 hydroxy phenyl) penten (1) one (3).

9. 5 [3 phenyl 3 hydroxy propyl (2) amino] 1 (4 isopropyl phenyl) penten (1) one (3).

10. 5 [3 phenyl 3 hydroxy propyl (2) amino] 1 {6,6 dimethyl bicycle [3,1,1] heptene (2) yl- (2)} penten -'(1) one (3).

and

References Cited UNITED STATES PATENTS 2,251,287 8/1941 Lott 260340.5 3,211,792 10/1965 Osbond et a1 260-5705 3,225,095 12/1965 Thiele et al 260-5705 3,337,626 8/1967 Thiele et al 260570.5

NICHOLAS S. RIZZO, Primary Examiner.

I. H. 'I URNIPSEED, Assistant Examiner. 

